Novel 16-oximidomethylene-gonanes



United States Patent The invention relates to novel 16-oximidomethylenesteroids having an aromatic A-ring and which have the formula Z /\l i X/CH=NOH R- wherein R is selected from the group consisting of hydrogenand lower alkyl of 1 to 7 carbon atoms, R is selected from the groupconsisting of hydrogen and halogen and Z is alkyl of 1 to 4 carbonatoms. The invention also relates to a novel process for the preparationof the l6-oximidomethylene steroids of Formula I. The invention furtherrelates to novel hypocholesterolemic compositions and to a novel methodof treating hypercholesterolemia in mammals.

Our copending commonly assigned U.S. patent application Ser. No. 556,796filed on even date herewith with the title Novel Gonane Derivatives,describes steroids analogous to Formula I except that they possess a16,17- isoxazolino-17 hydroxyl grouping which possesshypocholesterolemic activity. The l6-oximidomethylene steroids ofFormula I have a very intense hypocholesterolemic acivity and a veryweak estrogenic activity and much weaker than that of the16,17-isoxazolino steroids of our copending application. For example,3-methoxy- 16; oximidomethylene A estratriene 17,3 01 has about one halfof the estrogenic activity of A '-(4',5'- 16,17) isoxazolino 3 methoxy-A estratriene- 17-ol.

It is an object of the invention to provide the novellfi-oximidornethylene steroids of Formula I.

It is another object of the invention to provide a novel process for thepreparation of the 16-oximidomethylene steroids of Formula I.

It is a further object of the invention to provide novelhypocholesterolemic compositions.

It is an additional object of the invention to provide a novel method oftreating hypercholesterolemia in mammals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

The novel Idoximidomethylene steroids of the invention have thefollowing formula wherein R is selected from the group consisting ofhydrogen and lower alkyl of 1 to 7 carbon atoms, R is selected from thegroup consisting of hydrogen and halogen 3,409,722 Patented Nov. 5, 1968ice and Z is alkyl of 1 to 4 carbon atoms, R, may be a halogen such asfluorine, chlorine, bromine and iodine.

The process of the invention for the preparation of thel6-oximidomethylene steroids of Formula I comprises reducing withlithium aluminum hydride a 16,17- isoxazolino steroid of the formulawherein R, R and Z have the above definitions to obtain a16-oximidomethylene steroid of Formula I and recovering the latter.

Originally, we believe that the product resulting from the reduction ofthe C=N-- group of the compounds of Formula II resulted in aheterocyclic dihydroisoxazolino group of the formula and this was theformula indicated in our French Convention application. Subsequentanalysis has established that the reduction of the hemiacetal group ofthe isoxazolino group resulted in the opening of the ring to form16-oximidomethylene steroids of the Formula I.

The starting 16,17-isoxazolino steroids can be prepared according to theprocess described in our abovementioned copending US. patent applicationwhich comprises reacting a 2-R-3-OR -13-Z-16-hydroxymethylene- A-gonatriene-l7-one with hydroxylamine or an acid addition salt thereofto form the corresponding 16,17- isoxazolino steroid of Formula II.

The novel hypocholesterolemic compositions of the invention arecomprised of at least one 16-oximidomethylene steroid of the formulawherein R is selected from the group consisting of hydrogen and loweralkyl of 1 to 7 carbon atoms, R is selected from the group consisting ofhydrogen and halogen and Z is alkyl of 1 to 4 carbon atoms and a majoramount of a pharmaceutical carrier. The said compositions may be in theform of injectable solutions or suspensions, in ampules, in multipledose flacons, in the form of tablets, coated tablets, sublingualtablets, capsules and suppositories prepared in the usual manner. Thesaid steroids may be administered orally, perlingually, transcutaneouslyor rectally. The usual daily dosage is between 207 to 400 'y/kg. in theadult depending upon the method of administration.

Due to their intense hypocholesterolemic activity with very lowestrogenic activity, the steroids of Formula I are useful for thetreatment of hypercholesterolemia. They are useful for the preventionand cure of arterial disorders, cerebral arteritis, aortitis,coronaritis, chest angina and atheromatosis.

EXAMPLE Preparation of 3-methoxy-l6-oximidomethylene- A-estratriene-17,8-01

Step A.Preparation of A '-(4',5',16,17)-isoxazolino- 3-methoxy A-estratriene-l7-ol:

5 gm. of 3-methoxy-16-hydroxymethylene-A estratriene-17-one, preparedaccording to the process of Ru'ggieri et a1. (Gazz. vol. 93, 1963, p.269), were admixed with 150 cc. of ethanol and 1.45 gm. of hydroxylaminehydrochloride and the resulting mixture was held at reflux for 1 hour.Then, the reaction mixture was cooled to 20 C., neutralized with 2 cc.of triethylamine and concentrated to a volume of 50 cc. under vacuumwith stirring. 150 cc. of water were added thereto and the mixture wascooled. The precipitate obtained was vacuum filtered, washed with wateruntil the wash waters were neutral and dried under vacuum to obtain 5.23gm. of raw product which was purified by recrystallization from ethylacetate to obtain 2.31 gm. (44% yield) of A -(4,5- 16,17)-isoxazolino-3methoxy A -estratrienel 7 {-01, having a melting point of 241-242 C. anda specific rotation of [u] =+113 (c=0.8% in dimethylformamide).

The product occurred in the form of crystalline needles which wereslightly soluble in alcohol and insoluble in water.

AnaZysis.-C H O N; molecular weight=327.4l. Calculated: C, 73.37%; H,7.70%; N, 4.28%. Found: C, 73.3%; H, 7.7%; N, 4.2%.

Step B.-Preparation of 3-methoxy-l6g-oximidomethylene A-estratriene-175-01:

200 cc. of tetrahydrofuran and 160 cc. of ether were added to 4 gm. of A'-(4',5-16,17)-isoxazolino-3methoxy-A -estratriene-l7-ol and after thesuspension was brought to a temperature of C., 4 gm. of lithium aluminumhydride were slowly added thereto. The reaction mixture was maintainedat the tempertaure from 0 C. to for 30 minutes, after which the excessof the lithium aluminum hydride was destroyed by the addition of cc. ofethyl acetate. Then, about 100 cc. of a saturated solution of sodiumchloride were slowly added to the reaction mixture under stirring. Theresulting organic phase was decanted, washed with a saturated solutionofsodium chloride, dried over sodium sulfate, filtered and evaporated todryness under vacuum to obtain 4.700 gm. of a raw product which wassubjected to chromatography through silica gel and the product waseluted with methylene chloride containing 1% of methanol to obtain 2.500gm. of product having a melting point of 187188 C. The said product wasfurther purified by recrystallization from ethyl acetate to obtain 1.700gm. of 3-methoxy- 16g oximidomethylene-A -estratriene-17 3-01 having amelting point of 188 C. and a specific rotation of [oz] +39 (c=0.8% indimethylformamide).

The said product occurred in the form of colorless, crystalline needleswhich were soluble in pyridine and insoluble in water, alcohol, ether,benzene and chloroform.

Analysis.-C H O N; molecular weight=329.42. Calculated: C, 72.92%; H,8.26%; N, 4.25%. Found: C, 72.8%; H, 8.3%; N, 4.2%.

. 4 K This product is not described in the literature. H Using the sameprocedure, A -(4',5-l6,l7) isoxazo lino-2-fluoro-A-estratriene-3,17-diol, A -(4',5'-l6, 17) isoxazolino-13,B-ethyl-A-gonatriene-3,l7-diol can be converted to 2 fluoro 16 oximidomethylene-A -estratriene-3,l7/8-diol and l3B-ethyl,-16-oximidomethylene-A!-gonatriene-3,lflfi-diol respectively.

PHARMACOLOGICAL DATA I (1) Hypocholesterolemic action on the female ratThe work was carried out on groups'of female rats having an averageweight of 200 gm. 3-methoxy-l6f-oximidomethylene-N -estratriene-1713-01was administered orally in aqueous suspension to the animalsrat dailydoses of 50 and 'y/kg. for a period of 10 days. An-

other group of female rats of same age and weight-served as control.Samples of blood were taken on the 11th day with a view to determine theamount of seric sterols. The animals were sacrificed on the same day andthe uterus, liver and suparenal glands were separated and weighed. Thedecrease in the amount of the seric sterols was 37% at the dose of 50'y/kg. per day, and 42% at the dose of 100 'y/kg. per day whichdemonstrates that the said compound has a significanthypocholesterolemic activity.

(2) Investigation of estrogenic activityAllen-Doisy Test 3 methoxy16-oximidomethylene-A -estratriene-l7/3-ol in an aqueous dispersant wasadministered orally to groups of castrated female rats at varying doses.Vaginal smears were taken each day starting from the second day oftreatment for a period of seven days. Only those smears formedexclusively of keratinized cells were retained as positive. The rat unitfor the said product was about 2 mg. to a rat unit of 1 mg. for A-(4,5'-16,17)- isoxazolino-3-methoxy-A -estratriene-17-0l.

Various modifications of the compounds and process of the invention maybe made without departing from the spirit or scope thereof and it is tobeunderstood that the invention is to be limtied only as defined in theappended claims.

We claim:

1. A 16 {-oximidomethylene steriod of the formula wherein R is selectedfrom the group consisting of hydrogen and lower alkyl of 1 to 7 carbonatoms, R is selected from the group consisting of hydrogen and halogenand Z is alkyl to l to 4 carbon atoms to obtain the corresponding16-oximidomethylene steroid.

5. The process of claim 4 wherein Z is methyl.

6. A hypocholesterolemic composition comprising at least onel6g-oximidomethylene steroid of claim 1 and a major amount of apharmaceutical carrier.

7. A composition of claim 6 wherein Z is methyl.

8. A composition of claim 6 wherein the steroid is B-methoxy 16goximidomethylene A est-ratriene-17B-ol.

9. A method of treating hypercholesterolemia in mammals which comprisesadministering to the mammals an effective amount of at least one16-oximidornethylene steroid of claim 1.

10. The method of claim 9 wherein Z is methyl.

11. The method of claim 9 wherein the steroid is 3 methoxy 16oximidomethylene A estratriene-17,8-ol.

12. A 3 R -l6f-alkoximidomethylene-13-Z-A gonatriene-17;3-0l of theformula wherein R is selected from the group consisting of hydrogen andlower alkyl of 1 to 7 carbon atoms, R is selected from the groupconsisting of hydrogen, Z is alkyl of 1 to 4 carbon atoms and R is loweralkyl of 1 to 4 carbon atoms.

13. A compound of claim 11 which is 3-methoxy-16grnethoximidomet-hylene13B methyl M33500) gonatriene-l7fl-ol.

References Cited UNITED STATES PATENTS 3,030,357 4/1962 Clinton. H. A.FRENCH, Primary Examiner.

1. A 16$-OXIMIDOMETHYLENE STERIOD OF THE FORMULA
 9. A METHOD OF TREATINGHYPERCHOLESTEROLEMIA IN MAMMALS WHICH COMPRISES ADMINISTERING TO THEMAMMALS AN EFFECTIVE AMOUNT OF AT LEAST ONE 16$-OXIMIDOMETHYLENE STEROIDOF CLAIM 1.